Project Summary/Abstract The annual incidence of head and neck cancers worldwide is more than 550,000 cases with around 300,000 deaths each year, and it is estimated that in 2018 there will be 72,240 new cases of non-Hodgkin lymphoma with an estimated 20,140 deaths this year. In this proposal, we describe a strategy to use a novel subset of natural killer cells (g-NK cells) allogeneically for cancer therapy. We hypothesize that expansion and adoptive transfer of g-NK cells, concurrent with a targeting therapeutic mAb, will result in clinically meaningful responses in vivo. Importantly, because adoptive transfer of NK cells in humans does not result in severe graft-versus- host disease (GVHD) ? like reactions when given in an allogenic context (unlike adoptive T cells transfers) 9, we propose that this antibody-directed NK cell therapy could be given in an ?off-the-shelf? manner and, as such, be more broadly applicable for clinical use. The studies proposed in this application will establish the necessary expansion protocols and in vivo proof-of-concept results necessary for clinical development of this strategy. Indapta Therapeutics, Inc. (`Indapta') has entered into a relationship with the Stanford University to develop and test a next-generation cancer therapy. Indapta aims to become a leader in safe and effective cellular immuno-oncology therapy by building on a novel discovery by professors from Stanford and UC Davis. They are confirming a unique synergy between monoclonal antibodies (mAbs) and a specific and potent variety of `natural killer' (NK) immune cell lacking the Fc?RI? adapter (the g-NK cell). The scientific premise is that the conventional NK cells that have mutated after coming into contact with CMV to be lacking the Fc?RI? adapter (G-NK) will significantly increase ADCC and favorable apoptosis in the presence of a MAB to increase tumor killing. The product will combine these special g-NK cells with a targeting mAb, cetuximab for head and neck cancer and rituximab for lymphoma to destroy these cancer cells with high precision and efficacy. Indapta owns the exclusive license to the patents protecting this technology. The PI for this grant is Dr. John Sunwoo PhD in Immunology from Stanford. The CEO of Indapta has secured two NCI SBIR Fast-Track grants and one Phase 2b commercialization grant totaling $7.6M for his first company, which has attracted over $93M in venture funding as it moves to commercialize its early-stage technology. The Stanford and UC Davis team include leaders in NK cell therapy and a translational scientist at UCSF with extensive expertise in preclinical NK cell models. Indapta's product, pairs g-NK cells with mAbs cetuximab and rituximab to target head and neck and lymphoma cancers. This pairing enables us to (i) harness the high potency of g-NK cells, (ii) identify cancer cells by using a specialized mAb, (cetuximab and rituximab), (iii) lower the risk of adverse immune response, a feature of genetically engineered immunotherapies, because g-NK cells occur naturally, and (iv) benefit from the longevity (4-9 months) of g-NK cells as compared to conventional NK cells (~2 weeks), thereby reducing frequency of infusions as part of the immunologic regimen.